Tumor localization by Prostate Imaging and Reporting and Data System (PI-RADS) version 2.1 predicts prognosis of prostate cancer after radical prostatectomy

An improved reading agreement rate has been reported in version 2.1 (v2.1) of the Prostate Imaging and Reporting and Data System (PI-RADS) compared with earlier versions. To determine the predictive efficacy of bi-parametric MRI (bp-MRI) for biochemical recurrence (BCR), our study assessed PI-RADS v2.1 score and tumor location in Japanese prostate cancer patients who underwent radical prostatectomy. Retrospective analysis was performed on the clinical data of 299 patients who underwent radical prostatectomy at Chiba University Hospital between 2006 and 2018. The median prostate-specific antigen (PSA) level before surgery was 7.6 ng/mL. Preoperative PI-RADS v2.1 categories were 1–2, 3, 4, and 5 in 35, 56, 138, and 70 patients, respectively. Tumor location on preoperative MRI was 107 in the transition zone (TZ) and 192 in the peripheral zone (PZ). BCR-free survival was significantly shorter in the PZ group (p = 0.001). In the total prostatectomy specimens, preoperative PI-RADS category 5, radiological tumor location, pathological seminal vesicle invasion, and Grade Group ≥ 3 were independent prognostic factors of BCR. These four risk factors have significant potential to stratify patients and predict prognosis. Radiological tumor location and PI-RADS v2.1 category using bp-MRI may enable prediction of BCR following radical prostatectomy.

www.nature.com/scientificreports/ to the background. For a case with T2W score of 2, if the DWI score is 4 or 5, the overall PI-RADS category is upgraded from 2 to 3.
A previous study has indicated the equivalent utility of bi-parametric MRI (bp-MRI) and multi-parametric MRI (mp-MRI) 7 . The clinical value of PI-RADS v2.0 with bp-MRI and pathological Grade Group to predict BCR following radical prostatectomy also has been reported 8 . Patients with renal dysfunction or an allergy to contrast agent are not able to undergo dynamic contrast-enhanced (DCE) MRI. Investigation of a method for detection of prostate cancer in these patients is a pressing clinical issue. In this regard, bp-MRI can be used without contrast agent for imaging prostate tumors. Although PI-RADS v2.1 based on MRI has become the standard option for evaluation of the prostate, as yet there is limited evidence regarding PI-RADS v2.1 and the prediction of BCR after prostatectomy, particularly for bp-MRI. There is also evidence that tumor location influences the prognosis of localized prostate cancer 9 . Based on this evidence, we hypothesize that tumor location as well as MRI findings influence the outcome of radical prostatectomy.
Therefore, the aim of the present study was to examine the prognostic significance of the bp-MRI findings of prostate cancer for BCR, including location and PI-RADS v2.1 category.
Forty-eight patients (16.1%) experienced BCR during the observation period. Baseline PSA, PI-RADS category, radiological location, Pathological Grade Group, resection margin positive (RM+), and seminal vesicle invasion positive (SV+) results were significantly different between the two groups of patients with or without biochemical failure (Table 2).
Prognostic model for BCR using v2.1. We propose a new scoring system that classifies the risk categories by the four factors (Pathological Grade Group ≥ 3, radiological location at PZ, seminal vesicle invasion, and PI-RADS category 5) predictive of BCR after radical prostatectomy ( Fig. 2A). One point is assigned for each positive factor, and the points are summed to give the total score. We divided the patients into three groups according to the summed score, as follows: score 0-2, low-risk group; 3 points, intermediate-risk group; and 4 points, high-risk group. There were 248 (82.9%), 39 (13.0%), and 12 (4.0%) patients in the low-, intermediate-, and high-risk groups, respectively. The Kaplan-Meier method was used to evaluate prognosis. Prognosis for BCR was the worst in the high-risk group. This novel prognostic model for BCR, which takes into account PI-RADS v2.1 as well as clinical factors, enables differentiation of patients according to risk factors for PFS between high-and intermediate-risk (p = 0.0065), intermediate-and low-risk (p < 0.0001), and low-and high-risk groups (p < 0.0001) (Fig. 2B).
Radiological location as a preoperative predictive factor. Radiological location in the PZ was a worse prognostic factor than in the TZ (Fig. 1A). Patients with tumors in the radiological TZ had a lower BCR rate (7.5%) compared with those in the radiological PZ (20.8%) (p = 0.0075) ( Table 2). We divided patients into two groups according to the radiological location (radiological TZ and PZ groups).
The univariate Cox proportional hazard model found no factors of significance for BCR in the TZ group, whereas the PZ group showed significant differences in terms of EPE positive (p < 0.0001), RM positive (p < 0.0001), SV positive (p < 0.0001), GG ≥ 3 (p = 0.0003), lymph node metastases (p = 0.0388), and PI-RADS   (Table 4). It appears that preoperative PI-RADS location can predict the incidence of postoperative BCR. Patients with tumor in the radiological PZ region are more likely to suffer BCR if this finding is combined with the above four factors (RM positive, SV positive, Grade group ≥ 3, and PI-RADS category 5) following radical prostatectomy.
Effect of radiological localization on efficacy of predictive factors. Tumors located in the TZ had a better prognosis for BCR (Table 4). Kaplan-Meier analysis among the radiological PZ tumors identified PI-RADS category 5 (p < 0.0001) and Grade Group ≥ 3 (p < 0.0001) as significant factors predictive of BCR. For tumors located in the TZ, neither of these factors was predictive of BCR (p = 0.6702 and p = 0.2890, respectively) (Fig. 3).
These results indicate that Grade group ≥ 3 and PI-RADS category 5 could be used to assess the likely occurrence of BCR in PZ tumors, and show that the efficacy of the predictive factors varies according to the radiological location.

Discussion
The present study is the first to report that BCR after radical prostatectomy can be predicted by preoperative MRI tumor location evaluated by PI-RADS v2.1. Our results showed that zonal location of the tumor on preoperative MRI was a significant predictor of BCR. Based on the factors remaining by multivariate analysis for prediction of BCR, we propose a novel risk-classification model based on the following: PZ lesion on MRI, Pathological Grade Group ≥ 3, seminal vesicle invasion, and PI-RADS category 5. Classification of patients into the low-risk (0-2 points), intermediate-risk (3 points), and high-risk (4 points) groups predicted the prognosis of localized prostate cancer patients with statistically significant accuracy. The proposed risk classification system may contribute to the development of treatment strategies for localized prostate cancer.
Takahashi et al. reported that in radical prostatectomy specimens of Japanese patients, approximately 40% of prostate cancer originated in the TZ 10 . Compared to Caucasian men, Japanese patients had a greater incidence of TZ cancer. The pathological characteristics of TZ and PZ cancer are similar except for pathological T stage in www.nature.com/scientificreports/ the case of autopsy and cystoprostatectomy for bladder cancer 11 . TZ cancers are associated with decreased odds of adverse pathological findings and demonstrate improved recurrence-free survival. These favorable outcomes appear to be the result of different tumor biology 12 . Understanding the biology of tumors originating in different prostate zones will enable zone-specific therapies 13 . The present study revealed that for prediction of BCR, the efficacy of Grade group ≥ 3 and PI-RADS category 5 differed between the radiological TZ and PZ. This risk criterion may predict BCR after radical prostatectomy and enable optimization of zone-specific therapeutic strategy. As discussed in a previous report 13 , zone-specific strategies may be considered when choosing between active surveillance, radical prostatectomy, and extended lymph node dissection in patients with Gleason Score and T stage in the same category but in different location. The rationale for the zone-specific strategy may be explained by the difference in the genetic background and biomarker between TZ and PZ, which will lead to the difference in the therapeutic response and prognosis 13 . Previous studies have shown that seminal vesicle invasion and extraprostatic extension predict BCR after radical prostatectomy are related to predictive factors [14][15][16] . A positive surgical margin affects the incidence of BCR 17,18 . BCR risk is significantly higher for posterior-positive surgical margin than for other positive surgical margins 19 . Broad and anterior positive surgical margin has the highest risk of recurrence after radical perineal prostatectomy 20 . Prognosis was worse in the case of positive seminal vesicle invasion on preoperative MRI compared with negative seminal vesicle invasion 21 .
Several reports have evaluated oncological outcomes in patients with negative mp-MRI. Vinayak reported that patients with negative MRI findings (PI-RADS v2.0 score ≤ 2) who underwent radical prostatectomy had oncological outcomes comparable with positive MRI findings (PI-RADS v2.0 score ≥ 3) in terms of clinically significant prostate cancer rates, positive surgical margins, and BCR rates 22 . Shin et al. assessed patients with PI-RADS categories 4-5 on preoperative MRI who underwent prostatectomy and concluded that prognosis was predicted by the location of the lesion on preoperative MRI 23 .
In the present study, we analyzed patients with PI-RADS categories 1-5, not just categories 4-5. We found that prognosis was predicted by tumor location in PI-RADS v2.1 category 5 by MRI. To the best of our knowledge,  www.nature.com/scientificreports/ this is the first study to report the ability of zonal location on preoperative MRI to predict post-operative BCR of prostate cancer using PI-RADS v2.1.

Differences in evaluation between PI-RADS v2.0 and PI-RADS v2.1.
There are three significant differences between PI-RADS v2.1 and v2.0 in evaluating scoring. First, the definitions of scores 1 and 2 have been revised for TZ lesions on T2WI. Second, on evaluating the total score in TZ, a DWI score of 4 or 5 elevates the overall PI-RADS assessment category from 2 to 3 for lesions receiving a T2WI score of 2. Third, the definitions for DWI scores of 2 and 3 have been revised for lesions located in TZ/PZ. As PI-RADS v2.1 improves interreader reproducibility, these revisions may contribute to increased diagnostic performance 6,24 . We have previously reported that bp-MRI and Grade Group predict BCR after radical prostatectomy 8 . In the present study, we analyzed the predictive ability of location on preoperative MRI and evaluation using the new categorization in PI-RADS v2.1 in a large number of patients who underwent radical prostatectomy. In our study, changing to the PI-RADS v2.1 criteria resulted in a change in classification for 40 of the 299 patients. The data of these 40 patients are summarized in Supplementary Table 1.
Limitations. There are several limitations of this study. First, the number of patients analyzed was relatively limited and the evaluations were performed retrospectively. We plan to confirm our results in multi-institutional and prospective settings. Second, the median follow-up period was 49.8 months, and thus assessment related to survival was inadequate. It is necessary to assess oncological outcomes in a longer term. Third, surgery was performed mainly by three surgeons. The differences in prognosis may have been affected by the surgeons' skills. Finally, patients of a single Asian race were investigated in our study. The incidence of and deaths due to prostate cancer are lower in the Asian population than in the Western population 25 , which might have some impact on the generalizability of our results.

Conclusion
To the best of our knowledge, this is the first report to evaluate the risk of BCR by radiological tumor location by PI-RADS v2.1 category on preoperative MRI and by pathological diagnosis. We propose a novel risk-classification model based on the following independent risk factors: PZ location on MRI, Pathological Grade Group ≥ 3, seminal vesicle invasion, and PI-RADS category 5. This risk model could be applied to constructing and optimizing treatment strategies for patients with localized prostate cancer.   26 , we defined BCR as an elevation in PSA of ≥ 0.2 ng/mL after radical prostatectomy, which was confirmed in two consecutive measurements obtained at least 2 weeks apart. We defined the operation date as the date of PSA failure if PSA was ≥ 0.2 ng/mL after radical prostatectomy. MRI protocol. All enrolled patients underwent prostate MRI at 3 T prior to prostate biopsy. MRI was obtained with T1-weighted, T2-weighted, and diffusion-weighted imaging (DWI), and apparent diffusion coefficient maps were generated with b values of 0 and 1000 s/mm 2 . We used a high b-value (b = 2000) for DWI. bp-MRI comprised T2-weighted imaging and DWI. The radiologist used both bp-MRI and the apparent diffusion coefficient maps to determine the PI-RADS score.
PI-RADS v2.1. The PI-RADS scores were evaluated on non-contrast-enhanced bp-MRI by one radiologist (T.H.) with over 10 years of experience in diagnostic radiology. Using the scoring method of PI-RADS v2.1, each patient's score was recorded using a 5-point scale (1)(2)(3)(4)(5) and the zonal location. PI-RADS v2.1 was designed to improve detection, location, characterization, and risk stratification in patients with suspected cancer in treatment-naive prostate glands, with the overall objective of improving outcomes for patients. The changes incorporated in PI-RADS v2.1 were revised scoring of DWI in all zones in categories 2-3, and scoring of the overall assessment category in TZ. In TZ, a DWI score of 4 or 5 elevates the overall PI-RADS assessment category from 2 to 3 for lesions that receive a T2W score of 2. PI-RADS v2.1 states that T2-weighted images should be evaluated in the axial plane and in at least one additional orthogonal plane 27 .

Statistical analysis.
We performed univariate and multivariate Cox proportional hazard analyses to evaluate hazard ratios for BCR-free survival. Cut-offs of continuous variables were selected according to median values. Hazard ratios and 95% confidence intervals were derived. Kaplan-Meier methods were used for survival analysis. Statistical analysis was performed using JMP 14.2.0 (SAS Institute, Cary, NC, USA). Significance was considered at p < 0.05.

Data availability
The data sets used and analyzed in the current study are available from the corresponding authors upon reasonable request.